Invasive brain interventions often result in complications and long recovery times. In addition, the delivery of therapeutic agents via the blood supply is often impossible because the Blood-Brain Barrier (BBB) protects the brain tissue from foreign molecules. Laboratory experiments and first clinical trials have shown that focused ultrasound (FUS) beams can be used for noninvasive interventions. However, the utilization of FUS in the brain has been seriously limited by the difficulty of delivering ultrasound through the skull bone. The hypothesis of this grant has been that trans-cranial therapeutic FUS exposures can be delivered noninvasively through an intact skull. This hypothesis has now been validated in multiple clinical studies that demonstrate that brain tissue can be noninvasively coagulated in the central part of the brain. During the current grant period, we furthered our initial research and developed methods to enhance FUS interaction with tissue using microbubbles, thus making whole brain sonications feasible. We have further studied the impact of ultrasound exposures on brain tissue and demonstrated chemotherapy delivery across the BBB. We have shown significant increases in animal survival with multiple treatments. We have shown similar gains by using targeted natural killer cells. We have also developed the methods for clinical BBB modulation for chemotherapy treatments using a current clinical device. Our study plan is to exploit our novel findings during this grant period and provide the methods for novel treatments. Our goals are: First, to utilize our method of super-resolution localization of individual microbubbles to explore the feasibility of micro-surgery and precision drug delivery. Second, to construct and test new array concepts that eliminate the need for a large waterbath and provide patient specific array geometry for repeated treatments. The impact of this research could be huge if even one of these new ideas could be translated to the clinic. For example, the methods proposed here could make tumor and epilepsy surgery available for a larger number of patients and the BBB modulation could increase the effectiveness of chemotherapy and potentially even provide treatments for patients with Alzheimer`s Disease.